Is RNF31 p.Ser41Phe (c.122C>T) pathogenic?

RNF31 p.Ser41Phe (c.122C>T) is classified Uncertain significance in RNF31 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-09). AlphaMissense: likely benign (0.1483); Ultra-rare (popmax 0.0108%, nfe).

How common is RNF31 p.Ser41Phe (c.122C>T) in the general population?

RNF31 p.Ser41Phe (c.122C>T) is ultra-rare (popmax 0.0108%, nfe) (gnomAD).

What do computational predictors say about RNF31 p.Ser41Phe (c.122C>T)?

AlphaMissense predicts likely benign (score 0.1483) — an in-silico prediction, not a clinical call.

RNF31 p.Ser41Phe

c.122C>T · rs766282567 · VCV1347879

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1483 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0108%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1483	likely benign
REVEL	0.134	moderately benign-leaning
SaProt	LLR -11.69	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 4,105 bp · p 0.0049 · regional, not allelic
Overall
CADD	25.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0108% European (non-Finnish) · 127/1,178,114 alleles

Filtering AF 0.00921% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00865%

Overall 0.00828% 133/1,606,516 alleles · ultra-rare exomes 128/1,454,302 · genomes 5/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0108%	9,277
Remaining individualsnot grpmax-eligible	0.00643%	15,549
Finnishnot grpmax-eligible	0.00165%	60,484
African / African-American	0.00134%	74,836

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: RNF31
Protein: p.Ser41Phe
Coding: c.122C>T
MANE Select: NM_017999
dbSNP: rs766282567
Type: single nucleotide variant
Location: chr14:24147820 (GRCh38)
Gene constraint: LOEUF 0.37 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.39 · 36 PDB
Residue 41: the 'polyubiquitin-binding' region

Full RNF31 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RNF31 p.Ser41Pro Uncertain significance ★ ⚠ same residue
RNF31 p.Ala251Val Uncertain significance ★★ ⚠ same type
RNF31 p.Ala350Gly Uncertain significance ★★ ⚠ same type
RNF31 p.Ala45Val Uncertain significance ★★ ⚠ same type
RNF31 p.Ala501Thr Uncertain significance ★★ ⚠ same type
RNF31 p.Ala503Ser Uncertain significance ★★ ⚠ same type
RNF31 p.Ala503Thr Uncertain significance ★★ ⚠ same type
RNF31 p.Ala539Val Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/rnf31-p-ser41phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown